Stress hormone may be ‘middle man’ in gut-brain communication

The stress hormone cortisol appears to mediate the link between a common type of gut bacteria and the levels of an abundant brain metabolite, according to a recent animal study in Gut Microbes.

The relationship between the abundancy of the bacterial genus Ruminococcus ​and brain concentration of the metabolite n-acetylaspartate (NAA)was found to be mediated by cortisol. The findings of the study in piglets, may have implications for the study of neurodevelopmental disorders such as autism, suggested the research team from the University of Illinois, Urbana.

The study’s original aim was to investigate predictive relationships between different types of gut bacteria and other brain metabolites and neurotransmitters. They found that Bacteroides ​was associated with higher serotonin in the piglets, while abundant Ruminococcus ​ was correlated with lower serotonin and cortisol.

"Initially, we set out to characterise relationships between the gut microbiota, blood biomarkers, and brain metabolites. But once we looked at the relationships identified in our study, they kept leading us to independently reported findings in the autism literature,” ​commented first author Austin Mudd.

The researchers discovered that higher Bacteroides​ predicted higher concentrations of myo-inositol (as did more abundant Clostridium) ​and creatine. Butyricimonas ​positively predicted NAA, while Ruminococcus ​was negatively correlated with NAA levels. Previous work has shown that brain concentrations of these metabolites are altered in individuals with autism.

"These brain metabolites have been found in altered states in individuals diagnosed with autism spectrum disorder (ASD), yet no previous studies have identified specific links between bacterial genera and these particular metabolites,"​ said Mudd.

The findings may be significant in identifying a mechanism to help explain certain characteristics of autism.

“We remain cautious and do not want to overstate our findings without support from clinical intervention trials, but we hypothesize that this could be a contributing factor to autism's heterogeneous symptoms,"​ Mudd says.

Cortisol mediation​

The researchers’ initial analysis unexpectedly identified the possibility of a three-way relationship between Ruminococcus​, cortisol, and NAA. To verify this, they used a statistical method known as ‘mediation analysis’. They found that serum cortisol mediated the relationship between faecal Ruminococcus​ abundance and brain NAA concentration. Thus, cortisol appears to be the medium through which the bacterium communicates with the brain to affect NAA levels indirectly.

"This mediation finding is interesting, in that it gives us insight into one way that the gut microbiota may be communicating with the brain. It can be used as a framework for developing future intervention studies which further support this proposed mechanism,"​ observed lead researcher Professor RyanDilger.

Previous research has shown that gut bacteria send signals to the brain via the vagus nerve and that vagus nerve activity is related to cortisol levels. Other researchers have also hypothesised that the frequently-observed gastrointestinal disturbances in ASD individuals might be linked to gut dysbiosis which could potentially lead to disruption of the gut-brain axis.

These study results pave the way for further research into possible links between Ruminococcus ​and brain development.

"We admit this approach is limited by only using predictive models. Therefore, the next step is to generate empirical evidence in a clinical setting. So it's important to state that we've only generated a hypothesis here, but it's exciting to consider the progress that may be made in the future based on our evidence in the pre-clinical pig model," ​concluded Dilger.